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Papers by Kevin Lawson

Journal of The Chemical Society-perkin Transactions 2, 2001

J. Chem. Soc., Perkin Trans. 2, 2001, 651-669 DOI:10.1039/B008495F (Review). Aromatic interaction... more J. Chem. Soc., Perkin Trans. 2, 2001, 651-669 DOI:10.1039/B008495F (Review). Aromatic interactions. Christopher A. Hunter*a, Kevin R. Lawsonb, Julie Perkinsa and Christopher J. Urchb. a Krebs Institute for Biomolecular Science ...

Journal of The American Chemical Society, 2005

A supramolecular approach has been used to investigate the free energies of intermolecular aromat... more A supramolecular approach has been used to investigate the free energies of intermolecular aromatic stacking interactions. Chemical double mutant cycles have been used to measure the effect of a range of substituents on face-to-face stacking interactions with phenyl and with pentafluorophenyl rings. Electrostatic effects dominate the trends in the interaction energy This document is

Chemistry-a European Journal, 2001

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromati... more A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Organic & Biomolecular Chemistry, 2007

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the f... more Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl 3 , and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the p-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the p-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents.

Chemistry-a European Journal, 2001

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromati... more A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Clinical and Experimental Hypertension, 1987

This report summarizes studies aimed to characterize pharmacologically, hemodynamically and bioch... more This report summarizes studies aimed to characterize pharmacologically, hemodynamically and biochemically DA-1 (fenoldopam) and DA-2 (quinpirole) dopamine receptor agonists in anesthetized rats. Fenoldopam (20 micrograms/kg/min i.v. over 15 min) and quinpirole (10 micrograms/kg/min i.v. over 15 min) share the common property of decreasing mean carotid artery blood pressure by lowering peripheral vascular resistance. Fenoldopam increased mesenteric and renal blood flows whereas quinpirole decreased the former blood flow, but enhanced the latter. These effects of quinpirole were antagonized selectively by S-sulpiride, but not SCH 23390; however, with fenoldopam the reverse was found. In chlorisondamine-pretreated rats with blood pressure supported by vasopressin, fenoldopam, but not quinpirole, caused hypotension. In nephrectomized rats, the blood pressure effects of fenoldopam (assessed as area under the infusion time-response curve) were more pronounced than in sham-operated controls. The hypotensive effects due to an i.v. bolus injection of fenoldopam, but not to acetylcholine, histamine, salbutamol or quinpirole, were significantly inhibited in rats pretreated with an infusion of fenoldopam. In pithed rats, quinpirole reduced the pressor responses to electrical stimulation of the spinal cord without affecting those to exogenous norepinephrine, angiotensin II or 5-hydroxytryptamine which, on the contrary, were inhibited by fenoldopam. The plasma renin activity (in intact rats) was reduced by quinpirole, but elevated by fenoldopam. The latter effect also occurred in pithed rats and was blocked by SCH 23390. Quinpirole lowered heart rate, whilst fenoldopam produced tachycardia. These effects of quinpirole and fenoldopam were significantly inhibited by S-sulpiride and SCH 23390, respectively. In chlorisondamine-pretreated rats quinpirole failed to change heart rate whereas fenoldopam still increased it. In conclusion, these results indicate that DA-1 and DA-2 dopamine receptor agonists can be easily discriminated on the basis of their cardiovascular profiles.

Journal of Autonomic Pharmacology, 1989

1 In the rat aortic ring with endothelium, suspended in a K+-free salt solution containing 1.25 m... more 1 In the rat aortic ring with endothelium, suspended in a K+-free salt solution containing 1.25 mM CaZ+, the concentration-response curve to K+ (2-50 mM) was characterized by an initial small contractile phase occurring at 2-5 mM (Em,, , =0.67 iZ 0.18 g, n= 9) followed by a plateau (4-8 mM) and then a secondary contractile response (EmaX2= 1.64 iZ 0.13 g).

Journal of The Chemical Society-perkin Transactions 2, 2001

J. Chem. Soc., Perkin Trans. 2, 2001, 651-669 DOI:10.1039/B008495F (Review). Aromatic interaction... more J. Chem. Soc., Perkin Trans. 2, 2001, 651-669 DOI:10.1039/B008495F (Review). Aromatic interactions. Christopher A. Hunter*a, Kevin R. Lawsonb, Julie Perkinsa and Christopher J. Urchb. a Krebs Institute for Biomolecular Science ...

Journal of The American Chemical Society, 2005

A supramolecular approach has been used to investigate the free energies of intermolecular aromat... more A supramolecular approach has been used to investigate the free energies of intermolecular aromatic stacking interactions. Chemical double mutant cycles have been used to measure the effect of a range of substituents on face-to-face stacking interactions with phenyl and with pentafluorophenyl rings. Electrostatic effects dominate the trends in the interaction energy This document is

Chemistry-a European Journal, 2001

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromati... more A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Organic & Biomolecular Chemistry, 2007

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the f... more Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl 3 , and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the p-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the p-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents.

Chemistry-a European Journal, 2001

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromati... more A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Clinical and Experimental Hypertension, 1987

This report summarizes studies aimed to characterize pharmacologically, hemodynamically and bioch... more This report summarizes studies aimed to characterize pharmacologically, hemodynamically and biochemically DA-1 (fenoldopam) and DA-2 (quinpirole) dopamine receptor agonists in anesthetized rats. Fenoldopam (20 micrograms/kg/min i.v. over 15 min) and quinpirole (10 micrograms/kg/min i.v. over 15 min) share the common property of decreasing mean carotid artery blood pressure by lowering peripheral vascular resistance. Fenoldopam increased mesenteric and renal blood flows whereas quinpirole decreased the former blood flow, but enhanced the latter. These effects of quinpirole were antagonized selectively by S-sulpiride, but not SCH 23390; however, with fenoldopam the reverse was found. In chlorisondamine-pretreated rats with blood pressure supported by vasopressin, fenoldopam, but not quinpirole, caused hypotension. In nephrectomized rats, the blood pressure effects of fenoldopam (assessed as area under the infusion time-response curve) were more pronounced than in sham-operated controls. The hypotensive effects due to an i.v. bolus injection of fenoldopam, but not to acetylcholine, histamine, salbutamol or quinpirole, were significantly inhibited in rats pretreated with an infusion of fenoldopam. In pithed rats, quinpirole reduced the pressor responses to electrical stimulation of the spinal cord without affecting those to exogenous norepinephrine, angiotensin II or 5-hydroxytryptamine which, on the contrary, were inhibited by fenoldopam. The plasma renin activity (in intact rats) was reduced by quinpirole, but elevated by fenoldopam. The latter effect also occurred in pithed rats and was blocked by SCH 23390. Quinpirole lowered heart rate, whilst fenoldopam produced tachycardia. These effects of quinpirole and fenoldopam were significantly inhibited by S-sulpiride and SCH 23390, respectively. In chlorisondamine-pretreated rats quinpirole failed to change heart rate whereas fenoldopam still increased it. In conclusion, these results indicate that DA-1 and DA-2 dopamine receptor agonists can be easily discriminated on the basis of their cardiovascular profiles.

Journal of Autonomic Pharmacology, 1989

1 In the rat aortic ring with endothelium, suspended in a K+-free salt solution containing 1.25 m... more 1 In the rat aortic ring with endothelium, suspended in a K+-free salt solution containing 1.25 mM CaZ+, the concentration-response curve to K+ (2-50 mM) was characterized by an initial small contractile phase occurring at 2-5 mM (Em,, , =0.67 iZ 0.18 g, n= 9) followed by a plateau (4-8 mM) and then a secondary contractile response (EmaX2= 1.64 iZ 0.13 g).